The perception of pain is more complicated than a direct transmission of signals from an injured part of the body to specific receptors in the brain, and wherein the pain perceived is proportional to the injury. Rather, damage to peripheral tissue and injury to nerves may cause alterations in the central neural structures involved in pain perception affecting subsequent pain sensitivity. This neuroplasticity may bring about a central sensitization in response to longer lasting noxious stimuli, which may manifest itself as e.g. chronic pain, i.e. that the perception of pain remains even after the noxious stimulus has stopped, or as hyperalgesia, i.e. an increased response to a stimulus, which is normally painful. On of the more mysterious and dramatic examples of this is the “phantom limb syndrome”, i.e. the persistence of pain that existed in a limb prior to its amputation. For a recent review of central neuroplasticity and pain see Melzack et al in Ann. N.Y. Acad. Sci., 933, 157-174, 2001.
Chronic pain, such as neuropathic pain manifests itself differently than other types of pain, e.g. somatic or visceral pain. The pain is often described as shooting, burning, pins and needles, numb or stabbing. Common causes of neuropathic pain include alcoholism, amputation, back, leg and hip problems, chemotherapy, diabetes, HIV, multiple sclerosis, spine surgery, and herpes zoster virus infection.
The central component to chronic pain may explain why chronic pain, such as e.g. neuropathic pain often responds poorly to classical analgesics, such as non-steroid anti-inflammatory drugs (NSAIDS) and opioid analgesics. Tricyclic antidepressants (TCA), typified by amitryline, have become standard for the treatment of neuropatic pain, and the effect is believed to be mediated by the combined inhibitory effect on the serotonin transporter and the norepinephrine transporter [Clin Ther., 26, 951-979, 2004]. More recently, the so-called dual action antidepressants having an inhibitory effect on both the serotonin and the norepinephrine reuptake have been used clinically for the treatment of neuropatic pain [Human Psychopharm., 19, S21-S25, 2004]. Examples of dual acting antidepressants are venlafaxine and duloxetine, and this class of antidepressants is often referred to as SNRT.
Data on the use of selective serotonin reuptake inhibitors (SSRI) for neuropathic pain is scarce, but generally suggest a limited effect [Bas. Clin. Pharmacol., 96, 399-409, 2005]. In fact, it has been hypothesised that SSRI's are only weakly antinociceptive in and of themselves but that inhibition of the serotonin transporter augments the antinociceptive effect of norepinephrine reuptake inhibition. This notion is supported by a review of 22 animal and five human studies showing that SNRI's have superior antinociceptive effect compared to norepinephrine reuptake inhibitors, which again are superior to SSRI [Pain Med. 4, 310-316, 2000].
Recent data on the 5-HT3 antagonist odansetron implies that 5-HT3 antagonists may have an analgesic effect and thus be useful in the treatment of neuropathic pain [Anesth. Analg., 97, 1474-1478, 2003].
The use of tricyclic antidepressants is, however, associated with known, anticholinergic side effects, such as e.g. drowsiness, anxiety, restlessness, and cognitive and memory difficulties. Hence, there is a need in the art to find alternative ways of treating neuropatic pain.
The international patent application published as WO 2003/029232 discloses e.g. the compound 4-[2-(4-methylphenylsulfanyl)phenyl]piperidine as a free base and the corresponding HCl salt. The compound is reported to be an inhibitor of the serotonin transporter and the serotonin receptor 2C (5-HT2C), and is said to be useful for the treatment of affective disorders, e.g. depression and anxiety.